Recent studies from our laboratory, utilizing cell-specific gene targeting, indicate that collecting duct (CD)-derived endothelin-1 (ET-1) is an important regulator of systemic blood pressure and renal Na and water excretion. Based on this work, we hypothesize the following: CD ET-1 production is increased in conditions necessitating enhanced Na and water excretion and reduced blood pressure. Activation of CD ETB receptors and medullary interstitial cell ET receptors increases medullary nitric oxide and PGE2 production, while activation of CD ETA receptors enhances superoxide formation which reduces nitric oxide. Nitric oxide and PGE2 inhibit CD Na and/or water reabsorption and dilate medullary vasa recta. The resultant Na and water excretion limits hypertension in the setting of Na loading or mineralocorticoid excess. CD ET-1 may play a different role in angiotensin II hypertension due to angiotensin II down-regulation of the medullary ET-1 system. This system is also crucial in mediating vasopressin escape. Overall, the CD ET-1 system is essential in controlling blood pressure under normal physiologic as well as pathologic conditions. Mice with CD-specific knockout of ET-1, ETA receptor, ETB receptor, or both ETA and ETB receptors will be used. The mechanisms of ET-1 regulation of renal function and blood pressure under normal physiologic circumstances will be studied. This includes determination of whether CD-derived ET-1 acts in an autocrine and/or paracrine fashion, whether ETA and ETB receptors have opposing effects on Na and water excretion and blood pressure, whether and how CD-derived ET-1 regulates medullary blood flow, significance and mechanisms of CD-derived ET-1 interaction with nitric oxide, PGE2 and superoxide systems, and whether CD-derived ET-1 causes long-term changes in CD Na and water transporter expression. In addition, CD-derived ET-1 regulation of blood pressure and renal function under salt and/or water retaining conditions will be examined. This will include determination of the role of CD-derived ET-1 in controlling blood pressure and/or maintaining renal function in DOCA/salt hypertension, angiotensin II hypertension, and AVP excess. These studies will provide information on the role of CD-derived ET-1 in controlled blood pressure and renal function under normal physiologic as well as pathologic conditions. Such information is important in understanding intrarenal mechanisms responsible for hypertension and salt and water retention.